Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer’s Disease

Chen, Gong; Dai, Chun‐Ling; Liu, Fei; Iqbal, Khalid

doi:10.3389/fnagi.2022.837649

Cited by 48 publications

(35 citation statements)

References 66 publications

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“…), and environmental factors (e.g., education, social engagement, traumatic brain injury, etc.). Multi-target and combinatorial therapy are thus proposed to be more effective than single-target therapy for AD [ 168 , 169 , 170 , 171 ]. A combination therapy using donepezil and memantine has been approved by FDA for the treatment of moderate to severe AD [ 168 ].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

Gut Microbiota and Immunotherapy for Alzheimer’s Disease

Dai¹,

Liu²,

Iqbal³

et al. 2022

IJMS

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system in the peripheral and central nervous system through the microbiota–gut–brain axis. Growing evidence indicates that gut microbiota dysbiosis plays an important role in the pathogenesis of AD, and modulation of the gut microbiota may represent a new avenue for treating AD. Immunotherapy targeting Aβ and tau has emerged as the most promising disease-modifying therapy for the treatment of AD. However, the underlying mechanism of AD immunotherapy is not known. Importantly, preclinical and clinical studies have highlighted that the gut microbiota exerts a major influence on the efficacy of cancer immunotherapy. However, the role of the gut microbiota in AD immunotherapy has not been explored. We found that immunotherapy targeting tau can modulate the gut microbiota in an AD mouse model. In this article, we focused on the crosstalk between the gut microbiota, immunity, and AD immunotherapy. We speculate that modulation of the gut microbiota induced by AD immunotherapy may partially underlie the efficacy of the treatment.

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Section: Conclusion and Perspectivementioning

confidence: 99%

Gut Microbiota and Immunotherapy for Alzheimer’s Disease

Dai¹,

Liu²,

Iqbal³

et al. 2022

IJMS

Self Cite

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“…AD is multifactorial and several therapeutic targets are currently being investigated [ 6 , 7 , 8 , 9 ]. This is the case for instance of the amyloid-β (Aβ) peptide [ 5 , 10 ] and the hyperphosphorylated Tau protein [ 11 , 12 ] that can assemble to form extracellular amyloid deposits and intracellular tangles, respectively.…”

Section: Introductionmentioning

confidence: 99%

Why the Ala-His-His Peptide Is an Appropriate Scaffold to Remove and Redox Silence Copper Ions from the Alzheimer’s-Related Aβ Peptide

et al. 2022

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The progressive, neurodegenerative Alzheimer’s disease (AD) is the most widespread dementia. Due to the ageing of the population and the current lack of molecules able to prevent or stop the disease, AD will be even more impactful for society in the future. AD is a multifactorial disease, and, among other factors, metal ions have been regarded as potential therapeutic targets. This is the case for the redox-competent Cu ions involved in the production of reactive oxygen species (ROS) when bound to the Alzheimer-related Aβ peptide, a process that contributes to the overall oxidative stress and inflammation observed in AD. Here, we made use of peptide ligands to stop the Cu(Aβ)-induced ROS production and we showed why the AHH sequence is fully appropriate, while the two parents, AH and AAH, are not. The AHH peptide keeps its beneficial ability against Cu(Aβ)-induced ROS, even in the presence of ZnII-competing ions and other biologically relevant ions. The detailed kinetic mechanism by which AHH could exert its action against Cu(Aβ)-induced ROS is also proposed.

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“…Then, the complexity of the AD physiopathology, together with various pathologies already in AD patients, suggests that traditional drugs are not viable for adequate therapeutic effect [ 5 , 6 ]. In this sense, recent reports have been focused on evaluated multitarget compounds as possible treatments for AD as a more appropriate approach [ 7 , 8 ]. An interesting bibliometric (1990–2020) was published recently describing the biological targets and mechanism of multitarget anti-Alzheimer’s drugs, the most important being Acetylcholinesterase (AChE), Butirilcholinesterase (BChE), monoamine oxidase A (MAO A) and monoamine oxidase B (MAO B), beta-secretase 1 (BACE1), oxidative stress (OS), biometals and amyloid beta (Aβ 1-42 ) aggregation, of which a binary combination is the most employed [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease

Rosales‐Hernández

Morales²,

Correa-Basurto³

et al. 2022

IJMS

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aβ1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a–v) were evaluated by docking simulations as inhibitors of AChE and Aβ1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aβ1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski’s rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aβ1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aβ1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.

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Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer’s Disease

Cited by 48 publications

References 66 publications

Gut Microbiota and Immunotherapy for Alzheimer’s Disease

Gut Microbiota and Immunotherapy for Alzheimer’s Disease

Why the Ala-His-His Peptide Is an Appropriate Scaffold to Remove and Redox Silence Copper Ions from the Alzheimer’s-Related Aβ Peptide

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease

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